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| Chemical name: | 2-(2'-((Dimethylamino)methyl)-4'-(3-[18F]fluoropropoxy)-phenylthio)benzenamine |  |
| Abbreviated name: | [18F]1, [18F]SERT-1 | |
| Synonym: | ||
| Agent category: | Compound | |
| Target: | Serotonin transporter | |
| Target category: | Transporter | |
| Method of detection: | PET | |
| Source of signal\contrast: | 18F | |
| Activation: | No | |
| Studies: |
| Click on the above structure for additional information in PubChem. |
[PubMed]
Serotonin (5-hydroxytryptamine, 5-HT) has diverse physiological roles as a neurotransmitter in the central nervous system (1). It is also a regulator of smooth muscle function and platelet aggregation. The brain 5-HT system has been implicated in several neuropsychiatric disorders, including major depression, anxiety, obsessive-compulsive disorder, and schizophrenia (2, 3). The serotonergic transmission is controlled in part by the serotonin transporter (SERT), which regulates the concentration of free, active 5-HT in the synaptic cleft. Citalopram, paroxetine, and fluoxetine were developed as selective SERT inhibitors to treat depression and anxiety disorders by blocking the reuptake of 5-HT [PubMed]. The blockade led to a higher 5-HT concentration in the synaptic cleft and subsequently to improved patient health.
trans-1,2,3,5,6,10-β-Hexahydro-6-[4-([11C]methylthio)phenyl[pyrrolo-[2,1-a]isoquinoline ([11C]McN5652) binds selectively to the SERT, and its regional distribution of binding in humans correlates well with the known distribution of the SERT in human brain (4). However, the usefulness of [11C]McN5652 is limited by its nonspecific binding and slow release from specific binding sites (5). [11C]N,N-Dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ([11C]DASB) was found to be a useful tracer for SERT imaging in animals and humans (6-9). It displayed a nanomolar affinity for SERT and a >1,000-fold affinity for SERT over the dopamine transporter (DAT) and the norepinephrine transporter (NET). Uptake in the SERT-rich brain regions was both saturable and selective for SERT. However, the potential widespread use of [11C]DASB is limited by the short half-life of 11C (20 min). 2-(2'-((Dimethylamino)methyl)-4'-(3-fluoropropoxy)-phenylthio)benzenamine was shown to be a selective inhibitor of SERT. 2-(2'-((Dimethylamino)methyl)-4'-(3-[18F]fluoropropoxy)-phenylthio)benzenamine ([18F]1) is being evaluated as a useful tool for SERT imaging.
[PubMed]
[18F]1 was synthesized by nucleophilic [18F]fluorination of its O-mesylated precursor in acetonitrile solution of K2CO3/Kryptofix222 for 3 min at 100ºC (10, 11). [18F]1 was purified with high-performance liquid chromatography with radiochemical yields of 10–35% (decay-corrected) in a total synthesis time of ~60 min. The specific activity was 11.84–251.6 GBq/μmol (0.32–6.8 Ci/μmol) at the end of synthesis with radiochemical purities of >97%.
[PubMed]
The transporter-binding affinity of 2-(2'-((dimethylamino)methyl)-4'-(3-fluoropropoxy)-phenylthio)benzenamine was evaluated with competitive radioaffinity assays for SERT, norepinephrine (NET), and dopamine (DAT) transporters using stably transfected cell lines (11). Binding affinity (Ki, nM) at SERT, NET, and DAT were 0.27, 11.9, and 299 nM, respectively. Selective binding of 2-(2'-((dimethylamino)methyl)-4'-(3-fluoropropoxy)-phenylthio)benzenamine to SERT over NET was also measured using rat cortical membranes with Ki values of 0.24 and 12.4 nM, respectively.
[PubMed]
Wang et al. (10) performed biodistribution studies in normal rats (n = 3 rats/group). Intravenous injection of [18F]1 in rats resulted in high uptake of radioactivity in the lungs (3.86% injected dose (ID)/g) and kidneys (3.93% ID/g) at 30 min after injection; less pronounced uptake was seen in the whole brain (1.23% ID/g). Uptake in the thalamus (0.64% ID/g), hippocampus (0.79% ID/g), striatum (0.90% ID/g), cortex (1.00% ID/g), and hypothalamus (1.22% ID/g) was higher than the cerebellum (0.35% ID/g) at 30 min. The brain region radioactivity was >75% blocked with pretreatment of IDAM (SERT inhibitor) except in the cerebellum, which indicates that SERT is low in the cerebellum and the cerebellum can be used as a reference region. Pretreatment with DAT inhibitor GBR12909 did not inhibit the regional accumulation, and pretreatment with NET inhibitor nisoxetine showed only marginal inhibition. Radioactivity cleared gradually over a period of 240 min from all organs except for bone. Ex vivo autoradiography studies showed selective accumulation in the olfactory tubercles, thalamus, hypothalamus, substantia nigra, superior colliculus, dorsal raphe, and medial raphe as the SERT inhibitors, escitalopram, and IDAM effectively blocked [18F]1 localization in these brain regions. PET analysis in rat brains was performed in rats after intravenous injection of 11.1 MBq (0.3 mCi) [18F]1. The thalamus, midbrain, and striatum were clearly visualized and peaked at 10–20 min after injection with minimal accumulation in the cerebellum. The thalamus/cerebellum, midbrain/cerebellum, and striatum/cerebellum ratios of 4–4.5 peaked at 100–110 min. Injection of escitalopram and IDAM at 75 min after tracer injection caused a marked drop in radioactivity levels in the thalamus, midbrain, and striatum.
MH68782
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